Second and Thirdgeneration Thrombolytic Drugs

The principal physiological activator of plasminogen in the blood, tissue-type plasminogen activator (t-PA, al-teplase) (Activase), has a high binding affinity for fibrin and produces, after IV administration, a fibrin-selective activation of plasminogen. This selectivity is not absolute; circulating plasminogen also may be activated by large doses or lengthy treatment. After intravenous administration, alteplase is more efficacious than strep-tokinase in establishing coronary reperfusion. At equief-fective thrombolytic doses, alteplase causes less fib-rinogenolysis than streptokinase, but bleeding occurs with a similar incidence. The rate of rethrombosis after t-PA is greater than after streptokinase, possibly because alteplase is rapidly cleared from the blood (half-life is 5 to 10 minutes), and several administrations may be warranted. Reocclusion may be lessened by administration of heparin and antiplatelet drugs. Alteplase is a product of recombinant DNA technology and consists predominantly of the single-chain form (recombinant human tissue-type plasminogen activator, rt-PA). Upon exposure to fibrin, rt-PA is converted to the two-chain dimer.

Two genetically engineered variants of human t-PA have better pharmacological properties than alteplase. Reteplase (Retavase) contains only the peptide domains required for fibrin binding and protease activity. These changes increase potency and speed the onset of action. Reteplase may penetrate further into the fibrin clot than alteplase. The half-life of the drug remains short, however. Tenecteplase (TNK-tPA) (TNKase) has a longer half-life than alteplase, binds more avidly to fibrin, and in contrast to many other thrombolytic agents, may be administered as an IV bolus.

Anistreplase (Eminase) consists of streptokinase in a noncovalent 1:1 complex with plasminogen.Anistreplase is catalytically inert because of acylation of the catalytic site of plasminogen. However, the affinity of plasmino-gen binding to fibrin is maintained. It has a long catalytic half-life (90 minutes), and the time required for nonen-zymatic deacylation lengthens its thrombolytic effect after IV injection. Anistreplase is more effective than streptokinase in establishing coronary reperfusion, but it causes considerable fibrinogenolysis and is antigenic.

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